Process for synthesis of alpha,beta-unsaturated ketones

ABSTRACT

A method for the synthesis of an α,β-unsaturated ketone useful for making substituted 1,4-dihydropyridines is described by reacting an aldehyde with pyrrolidine and then adding a ketone followed by trifluoroacetic acid at low temperature. The synthesis is used in a process for making substituted 1,4-dihydropyridines wherein a vinylogous amide is prepared by reacting a 1,3-cyclohexanedione with a phenylethylamine. The α,β-unsaturated ketone can be reacted with a vinylogous amide to form a 1,5-diketone which can be converted to a substituted 1,4-dihydropyridine.

FIELD OF THE INVENTION

[0001] This invention relates to a process for synthesis ofα,β-unsaturated ketones useful for the synthesis of substituted1,4-dihydropyridines which are useful as smooth muscle relaxants inmammals.

BACKGROUND ART

[0002] Inappropriate smooth muscle activation is believed to be involvedin urinary incontinence and in many other conditions and diseasesincluding, hypertension, asthma, peripheral vascular disease, rightheart failure, congestive heart failure, angina, ischemic heart disease,cerebrovascular disease, renal colic, disorders associated with kidneystones, irritable bowel syndrome, male-pattern baldness, prematurelabor, impotence and peptic ulcers.

[0003] It is known that urinary incontinence can occur becauseuncontrolled or unstable bladder contractions arise in excitable bladdertissue, so-called overactive bladder. Existing treatments for urinaryincontinence rely largely on drugs that were originally developed forother indications. One group of such drugs includes the calcium-channelblockers, an example of which is nifedipine(4-(2′-nitrophenyl)-2,6,-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine).Such drugs were originally developed and are primarily used asantianginal or antihypertensive cardiovascular agents.

[0004] Nifedipine is a member of a class of compounds known asdihydropyridines. Structural requirements for calcium blocking activityby dihydropyridines are now well established. Active compounds describedin Chapter 14.1 of the medicinal chemistry text book, ComprehensiveMedicinal Chemistry, Volume 3, Edited by John C. Emmett (Pergamon Press1990), possess a 1,4-dihydropyridine ring with an aryl group at the4-position and ester groups at the 3- and 5-positions.

[0005] A group of 1,4-dihydropyridine derivatives that are said to havestrong muscular spasmolytic effects, are disclosed in German Patent DE2003148. Such compounds include certain4,6,7,8-tetrahydro-5(1H)-quinolones that possess an ester or keto groupat the 3-position. A wide spectrum of pharmacological actions aredisclosed for the compounds including strong muscular spasmolyticeffects which become evident in the smooth musculature of thegastrointestinal tract, the urogenital tract and the respiratory system.Effects on the heart are also disclosed (a “heart-relieving” effect)with a reduction of the blood pressure of normotonic and hypertonicanimals.

[0006] Vitolinya et al, Khim.-Parm. Zh., 15(1), 39-42, 1981, havereported that3-cyano4-phenyl-2,7,7-trimethyl-4,6,7,8-tetrahydro-5(1H)-quinoloneblocks the spasmogenic effect of both acetylcholine and barium chlorideon intestinal smooth muscle and has hypotensive properties.

[0007] S. M. Jain et al, Indian Journal of Chemistry, Volume 30B,November, 1991, pages 1037-1040, discloses the synthesis andpharmacological screening of certain 9-(substitutedphenyl)-1,8-(2H,5H-)-acridinediones. The compounds are disclosed by Jainet al, as having varying degrees of hypotensive, anti-inflammatory andanti-implantation activities.

[0008] It is known that potassium channel opening compounds can relaxsmooth muscle tissue by functioning to open potassium channels. Forexample, D. A. Nurse et al, British Journal of Urology, (1991), 68,27-31, disclose that a well known potassium channel opener, cromakalim((−)-6-cyano-3,4-dydihydro-2,2-dimethyl-trans-4,(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol),has been found to be effective in a preliminary clinical trial for thetreatment of urinary incontinence. Accordingly, it is believed thatcompounds that function to open potassium channels in bladder cells andthereby relax bladder smooth muscle tissue, can prevent or ameliorateuncontrolled bladder contractions which can cause urinary incontinence.It is also known that urinary incontinence can be caused by uncontrolledor unstable bladder smooth muscle contractions and thatpotassium-channel opening compounds can cause relaxation of smoothmuscle and excitable bladder tissue. Accordingly, U.S. Pat. No.5,455,253 discloses a group of potassium-channel opening compounds, thatis, 4,6,7,8-tetrahydro-5(1H)-quinolones, their use in the treatment ofurinary incontinence in mammals (including man), and methods forpreparing the compounds and pharmaceutical compositions containing thecompounds.

DESCRIPTION OF THE INVENTION

[0009] The main aspect of the present invention provides a novelsynthetic process for making α,β-unsaturated ketones. Such a process isuseful in a synthesis of asymmetric substituted 1,4-dihydropyridinesthat is suitable for implementation on an industrial scale.

[0010] Advantageously, it has been found that an α,β-unsaturated ketonemay be prepared by the process of the present invention by reacting analdehyde with a ketone without the use of molecular sieves to effect thereaction of the reactants to form the product molecule. It has beenfound that an α,β-unsaturated ketone can be prepared by reacting analdehyde with a ketone in accordance with Scheme I. Accordingly, anobject of a process of the present invention is the synthesis ofα,β-unsaturated ketone by the reaction of an aldehyde with anamine-reagent such as pyrrolidine or another secondary amine such aspiperidine or morpholine, or a dialkylamine such as diethylamine indichloromethane at 0-10° C., followed by the addition of a ketone andthen trifluoroacetic acid while maintaining the temperature.

[0011] Without intending to be bound by the structures shown, it isenvisaged that the formation of an α,β-unsaturated ketone proceeds bythe formation of intermediates, as shown in the following scheme:

[0012] It has further been found that an inherently more-efficientprocess for synthesizing asymmetric vinylogous amides may be achieved byreacting a substituted or unsubstituted substantially homo-chiralphenylethylamine with a substituted or unsubstituted cyclohexanone or1,3-cyclohexanedione, thereby yielding a substantially homo-chiralvinylogous amide.

[0013] Advantageously, it has been found that the reaction of avinylogous amide with an α,β-unsaturated ketone is facilitated in thepresence of a silicon agent. Accordingly, an object of a process of thepresent invention is the synthesis of a substantially homo-chiral1,5-diketone useful for making, for example, 1,4-dihydropyridines.Advantageously, the process of the present invention does not require aclassical resolution of a racemic mixture as in other routes to thisclass of compound. These objects and advantages are achieved by theinventive process. Other objects and advantages will be obvious herefromto those of skill in the art.

[0014] Further, it has been found that an α,β-unsaturated ketone may beused to synthesize a substituted 1,4-dihydropyridine by three processsteps. First, a vinylogous amide is prepared by reacting a substitutedor unsubstituted 1,3-cyclohexanedione with a substituted orunsubstituted phenylethylamine; second, an α,β-unsaturated ketone isreacted with the vinylogous amide to form a 1,5-diketone, and, third,the 1,5-diketone is converted to a 1,4 dihydropyridine.

[0015] Using the process of the present invention, an asymmetricsubstituted 1,4-dihydropyridine is prepared by reacting a1,3-cyclohexanedione with a substantially homo-chiral phenylethylamineto yield an asymmetric vinylogous amide; the α,β-unsaturated ketone isthen reacted with the asymmetric vinylogous amide to form a1,5-diketone. Conversion of the 1,5-diketone to a 1,4-dihydropyridineyields a substantially homo-chiral product.

[0016] What follows describes the steps of a process for the synthesisof substituted 1,4 dihydropyridines utilizing the present invention.

[0017] Step A:

[0018] It has been unexpectedly found that when an aldehyde is reactedwith a secondary amine such as pyrrolidine in dichloromethane at 0-10°C., followed by the addition of a ketone and then trifluoroacetic acidwhile maintaining the temperature at −5 to 10° C., an α,β-unsaturatedketone is formed according to the following scheme:

[0019] In Formulae I and III, R¹ is selected from (C₁-C₆)alkyl, or arylwhere any alkyl or aryl moiety is unsubstituted or mono-, di- ortri-substituted with moieties independently selected from hydroxy, halo,and cyano; or

[0020] R¹ is a group of formula X,

[0021] wherein:

[0022] G and J are independently selected from hydrogen, hydroxy(C₁-C₄)alkoxy, nitro, cyano, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy,halo, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl, phenyl and (C₁-C₄)alkylsulphonyl,or G and J taken together are (C₁-C₄)alkylenedioxy; or

[0023] R¹ is 2-thienyl 4-substituted, 5-substituted or 4,5-substitutedwith E, or 3-thienyl or furyl 5-substituted with E where E isindependently selected from a group consisting of nitro, cyano, halo,(C₁-C₆)alkyl, (C₁-C₄)alkyl-sulphonyl and 2-thienyl; or

[0024] R¹ is a 2-pyridyl 4,5-substituted, 5-substituted or5,6-substituted with E; or

[0025] R¹ is a 3-pyridyl 6-substituted with E; or

[0026] R¹ is a 4-pyridyl 2-substituted with E.

[0027] Particular values of R¹ include methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,3-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl, phenyl,3-methoxyphenyl, 3-nitrophenyl, 3-cyanophenyl, 3-trifluoromethylphenyl,3-trifluoromethyl4-cyanophenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl,3-bromo-4-fluorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, and3,4-methylenedioxyphenyl.

[0028] Particular values of G include the particular values of J andethanoyl.

[0029] Particular values of J include hydrogen, hydroxy, methoxy, nitro,cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, iso-propyl andhalo.

[0030] Particularly R¹ is 3-nitrophenyl or 3-cyanophenyl, and mostpreferably, R¹ is 3-cyanophenyl.

[0031] Particular values of substituted 2-thienyl, 3-thienyl or furylmoieties include 4-bromo-2-thienyl, 5-bromo-2-thienyl,5-methylsulphonyl-2-thienyl, 5-methyl-2-thienyl,5-(2-thienyl)-2-thienyl, 4-nitro-2-thienyl, 5-nitro-2-thienyl,4-cyano-2-thienyl, and 5-nitro-3-thienyl.

[0032] In formulae I, II and III R² is hydrogen, (C₁-C₆)alkyl or mono-,di- or tri-halo(C₁-C₄)alkyl.

[0033] Particularly R² is methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl or trifluoromethyl; and mostpreferably, R² is trifluoromethyl.

[0034] In formulae II and III, R³ is hydrogen, cyano, (C₁-C₆)alkyl,(C₁-C₆)fluoroalkyl or ethanoyl and preferably R³ is hydrogen.

[0035] In formulae II and III, R² and R³, when taken together, can forma substituted or unsubstituted (C₁-C₆)cycloalkyl moiety whereparticularly R² and R³, when taken together are 1,4-butandiyl.

[0036] Step B:

[0037] A vinylogous amide is prepared by reacting a 1,3-cyclohexanedionewith a phenylethylamine, at reflux under Dean-Stark conditions. Thevinylogous amide is isolated by evaporation of the volatile componentsof the reaction mixture.

[0038] Particularly, it has been found that cyclohexanone,1,3-cyclohexanedione and substituted-cyclohexanone moieties may be usedin the present process together with phenylethylamine,substituted-phenylethylamines and substantially homo-chiralphenylethylamines.

[0039] Accordingly, performance of Step B with a substantiallyhomo-chiral phenylethylamine, e.g., (R)-(+)-1-phenylethylamine, yieldsan asymmetric vinylogous amide according to the following scheme:

[0040] In formulae IV and VI, R⁴ and R⁵ are independently selected fromhydrogen or (C₁-C₄)alkyl.

[0041] Particularly, in formulae IV and VI R⁴ and R⁵ are independentlyselected from hydrogen or methyl, and most particularly, R⁴ and R⁵ arehydrogen.

[0042] Step C:

[0043] Vinylogous amides are generally relatively unreactive, however,it has unexpectedly been found that in the presence of a silicon agentcapable of acting as a Lewis acid, reaction of a vinylogous amide withan α,β-unsaturated ketone is facilitated with the formation of a1,5-diketone. A silicon agent suitable to achieve this reaction istrimethylsilyl chloride. Other silicon agents suitable for use in thepresent invention are triethylsilyl chloride; triphenylsilyl chloride,trimethylsilyltriflate and tributylsilyl chloride.

[0044] Accordingly, it has been found that an asymmetric 1,5-diketonecan be made by preparing a solution of an α,β-unsaturated ketone andtrimethylsilyl chloride in acetonitrile and treating the mixture with anasymmetric vinylogous amide according to the following scheme:

[0045] In formulae III, VI and VII, R¹, R², R³, R⁴ and R⁵ have thevalues disclosed heretofore.

[0046] Without intending to be bound by theory, it is envisaged that inthe process of Step C, an α,β-unsaturated ketone in the presence of atrimethylsilyl chloride reacts with an asymmetric vinylogous amide toyield an intermediate of formula M which rearranges to anotherintermediate of formula XII, as shown below:

[0047] The intermediate, XII, is then believed to convert to the1,5-diketone product of formula VII, as follows:

[0048] Step D:

[0049] A 1,5-diketone is converted to a hemiaminal by treatment withaqueous ammonia in acetonitrile. The hemiaminal is then converted to a1,4-dihydropyridine by treatment with concentrated hydrochloric acidaccording to the following scheme:

[0050] While aqueous ammonia is preferred, it is envisaged thatconversion of a 1,5-diketone to a hemiaminal in Step D may otherwise beachieved by use of liquid or gaseous ammonia.

[0051] More particularly, the present invention provides a process ormethod for making an α,β-unsaturated ketone, comprising reacting analdehyde and a secondary amine selected from pyrrolidine, piperidine,morpholine and diethylamine, in dichloromethane at 0-10° C. to form anintermediate; adding a ketone, and reacting the intermediate with theketone by adding trifluoroacetic acid while maintaining the temperatureat 0-10° C., to form an α,β-unsaturated ketone.

[0052] In a particular aspect of the process the secondary amine ispyrrolidine.

[0053] In a further particular aspect of the process, the aldehyde is acompound of formula I

[0054] wherein:

[0055] R¹ is selected from (C₁-C₆)alkyl, or aryl where any alkyl or arylmoiety is unsubstituted or mono-, di- or tri-substituted with moietiesindependently selected from hydroxy, halo, and cyano; or

[0056] R¹ is a group of formula X,

[0057] wherein:

[0058] G and J are independently selected from hydrogen, hydroxy(C₁-C₄)alkoxy, nitro, cyano, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy,halo, (C₁-C₄)alkyl, (C₁-C₄)alkrnoyl, phenyl and (C₁-C₄)alkylsulphonyl,or G and J taken together are (C₁-C₄)alkylenedioxy; or

[0059] R¹ is 2-thienyl 4-substituted, 5-substituted or 4,5-substitutedwith E, or 3-thienyl or furyl 5-substituted with E where E isindependently selected from a group consisting of nitro, cyano, halo,(C₁-C₆)alkyl, (C₁-C₄)alkyl-sulphonyl and 2-thienyl, where “halo”includes bromo, chloro, fluoro and iodo; or

[0060] R¹ is a 2-pyridyl 4,5-substituted, 5-substituted or5,6-substituted with E; or

[0061] R¹ is a 3-pyridyl 6-substituted with E; or

[0062] R¹ is a 4-pyridyl 2-substituted with E;

[0063] the ketone is a compound of formula II,

[0064] wherein:

[0065] R² is selected from hydrogen, (C₁-C₆)alkyl and mono-, di- ortri-halo(C₁-C₄)alkyl;

[0066] R³ is selected from hydrogen, cyano, (C₁-C₆)alkyl,(C₁-C₆)fluoroalkyl and ethanoyl; or

[0067] R² and R³, when taken together, form a substituted orunsubstituted (C₁-C₆)cycloalkyl moiety, and

[0068] the α,β-unsaturated ketone is a compound of formula III,

[0069] In particular aspect of the process R¹ is selected from(C₁-C₆)alkyl, or aryl where any foregoing alkyl or aryl moiety can besubstituted with hydroxy, halo, or cyano; R² is selected from mono-, di-or tri-halo(C₁-C₄)alkyl; R³ is selected from hydrogen, cyano,(C₁-C₆)alkyl, (C₁-C₆)fluoroalkyl and ethanoyl, and R⁴ and R⁵ areindependently selected from hydrogen or methyl.

[0070] In still another aspect of the process, R¹ is selected frommethyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl,phenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-cyanophenyl,3-trifluoromethylphenyl, 3-trifluoromethyl-4-cyanophenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-bromophenyl, 4-fluorophenyl,4-chlorophenyl, 3-bromo-4-fluorophenyl, 3,4-dichlorophenyl,4-methylphenyl, and 3,4-methylenedioxyphenyl; R² is selected frommethyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl and trifluoromethyl; R³ is selected from hydrogen, cyano andethanoyl, and R⁴ and R⁵ are selected from hydrogen and methyl.

[0071] In a most particular aspect of the process, the aldehyde is3-cyanobenzaldehyde, and the ketone is 1,1,1-trifluoroacetone.

[0072] It will be appreciated by those of skill in the art that theinvention described herein provides a novel process for makingα,β-unsaturated ketones that may be utilized in the synthesis ofcompounds for which an (α,β-unsaturated ketone is an intermediate or aprecursor. It will also be appreciated that the invention also providesa novel process for the synthesis of an asymmetric product by achievingthe reaction of normally-unreactive asymmetric vinylogous amides withα,β-unsaturated ketones. Accordingly, it will be further appreciatedthat by employing a substantially homo-chiral substitutedphenylethylamine, either (R) or (S), to form the vinylogous amide, thedesired enantiomeric form of the 1,4-dihydropyridine product, may bedetermined. For example, if a substituted (R)-phenylethylamine is used,the 1,4-dihydropyridine produced has an (S) configuration.

[0073] While not intending to be bound by theory, it is believed thatcompounds made by the process of the present invention function toprevent or ameliorate uncontrolled bladder contractions, which can causeurinary incontinence, by opening potassium channels in bladder cells andthereby relax bladder smooth muscle tissue. Compounds made by theprocess of the present invention are therefore useful for relaxingbladder smooth muscle, thus preventing or ameliorating overactivebladder uncontrolled or unstable bladder contractions. Hence, theprocess of the present invention can be used to make compounds usefulfor the treatment of urge incontinence, which includes for exampledetrusor instability, which may result from cystitis, urethritis,tumors, stones, diverticuli or outflow obstruction; and detrusorhyperreflexia, which may result from stroke, dementia, Parkinson'sdisease, suprasacral spinal cord injury or suprasacral spinal corddisease. Some compounds that can be made by the present process havebeen found to possess the further unexpected property that they arecapable of acting selectively on the bladder without at the same timesignificantly affecting the cardiovascular system, as indicated by heartrate and blood pressure measurements Thus, these compounds may beparticularly useful to treat urinary incontinence in patients, such asfor example the elderly, for whom cardiovascular effects, such as ahypotensive effect, are particularly undesirable.

[0074] Thus, this invention provides to a novel process useful formaking a group of compounds which are useful in the treatment of bladderinstability in mammals such as man and for the treatment of urinaryincontinence in mammals including man.

[0075] Particularly, this invention provides a novel process useful formaking 1,4-dihydropyridines of formula VIII. It will be appreciated bythose of skill in the art, that compounds of formula VIII contain anasymmetric center, and, accordingly, may exist as, and be isolated as,optically-active and racemic forms. The present invention encompasses amethod for making a substantially enantiomerically-pure form of suchcompounds. Such enantiomerically-pure compounds possess propertiesuseful in the treatment of urinary incontinence, it being well known inthe art how to determine efficacy for the treatment of urinaryincontinence by standard tests. A description of such tests can be foundin U.S. Pat. No. 5,455,253, the disclosure of which is incorporatedherein by reference in its entirety.

[0076] Definitions:

[0077] As used herein, the terms “alkyl” and “alkoxy” include bothstraight and branched chain radicals, but it is to be understood thatreferences to individual radicals such as “propyl” or “propoxy” embraceonly the straight chain (“normal”) radical, branched chain isomers suchas “iso-propyl” or “iso-propoxy” being referred to specifically.

[0078] As used herein “halo” includes fluoro, chloro, bromo, and iodounless noted otherwise.

[0079] When used herein in the disclosure and the claims, ranges asapplied to temperatures, concentrations, times, values etc., whetherdisclosed as “10-25, ” “1 to 110” or the like, are to be read to includeall integral, and where appropriate non-integral, values within thestated range.

[0080] Particular values of (C₁-C₄)alkyl include methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl.

[0081] Particular values of (C₁-C₄)fluoroalkyl include trifluoromethyland pentafluoroethyl.

[0082] Particular values of (C₁-C₄)alkoxy include methoxy, ethoxy,propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0083] Particular values of (C₁-C₄)fluoroalkoxy include trifluoromethoxyand pentafluoroethoxy.

[0084] A particular value of (C₁-C₄)alkanoyl is ethanoyl.

[0085] A particular value of (C₁-C₄)alkylsulphonyl is methanesulphonyl.

[0086] Particular values for (C₁-C₃)alkylenedioxy are methylenedioxy andethylenedioxy.

Examples

[0087] The following examples illustrate how a process according to thepresent invention is carried out and how an α,β-unsaturated ketone canbe made by the present invention and how such α,β-unsaturated ketonescan be used to make other compounds. The examples provided herein areexemplary and are not to be regarded as limiting the scope of theinvention.

Example 1 3-(4,4,4-Trifluoro-3-oxo-1-butenyl)benzonitrile

[0088] 3-(4,4,4-Triluoro-3-oxo-1-butenyl)benzonitrile, (anα,β-unsaturated ketone) was made by reacting 3-cyanobenzaldehyde offormula Ia with 1,1,1-trifluoroacetone of formula IIa, to produce3-(4,4,4-trifluoro-3-oxo-1-butenyl)benzonitrile of formula ma, accordingto the following scheme:

[0089] 3-cyanobenzaldehyde in dichloromethane was cooled to 0-10° C.,and an amine-reagent such as pyrrolidine or another secondary amine suchas piperidine or morpholine, or a dialkylamine such as diethylaminecapable of effecting the particular transformation, was added and thereaction vessel stirred for 10 minutes or longer.1,1,1-trifluoroacetone, or an aqueous solution thereof, was then slowlyadded over about 30 minutes while keeping the temperature at −5-10° C.,and the vessel stirred for 3-5 hours. Trifluoroacetic acid, or anotherstrong acid such as methanesulfonic acid, was then slowly added over aperiod of at least 30 minutes while maintaining the temperature at−5-10° C. The vessel was stirred for 2-10 hours and then allowed toslowly warm for 5 hours to overnight at 20-30° C. The organic solventwas extracted twice with water, 5 volumes of tert-amylmethyl ether, oranother solvent such as tert-butylmethyl ether, toluene, or tert-butylacetate, were added and the organic solvent distilled off. The contentsof the vessel were then heated to 45-60° C., and about 3.5-6 volumes ofiso-hexane, or another suitable solvent such as heptane, cyclohexane oroctane, were slowly added over 10-40 minutes. The temperature of themixture was maintained at 45-60° C., for 10-60 minutes, and the mixturethen ramp-cooled over 30 or more minutes to 5-22° C. The reactionmixture was then stirred overnight, cooled to −3 to −8° C., and held atthat temperature for 3 or more hours until the α,β-unsaturated ketonecrystallized from the solvent. Solid α,β-unsaturated ketone wasrecovered by filtration.

Example 2 3-[(2-Oxocyclohexylidene)methyl]benzenecarbonitrile

[0090] 3-[(2-Oxocyclohexylidene)methyl]benzenecarbonitrile (anα,β-unsaturated ketone) was made by reacting an aldehyde of formula Iawith a ketone of formula IIb, to form3-[(2-oxocyclohexylidene)methyl]benzenecarbonitrile of formula IIIb asdescribed in Example 1, according to the following scheme:

[0091] To perform the reaction, the aldehyde in dichloromethane wascooled to 5° C., pyrrolidine was added, and the reaction vessel stirredfor 30 minutes. The ketone was slowly added over 60 minutes whilekeeping the temperature at 5° C., and stirring of the vessel wascontinued for 3.5 hours. Trifluoroacetic acid was then slowly added over60 minutes, the vessel stirred for 2 hours, and then allowed to warmovernight to 22° C. Purification of the product was achieved asdescribed in Example 1. In general, α,β-unsaturated ketones may befurther purified by crystallization from solvents and recovered assolids by filtration.

Example 3 (R)-3-[(1-Phenylethyl)amino]-2-Cyclohexen-1-One

[0092] (R)-3-[(1-Phenylethyl)amino]-2-cyclohexen-1-one, (a vinylogousamide) was made by reacting cyclohexane-1,3-dione of formula IVa with(R)-(+)-1-phenylethylamine of formula Va to form(R)-3-[(1-phenylethyl)amino]-2-cyclohexen-1-one of formula VIa,according to the following scheme:

[0093] Cyclohexane-1,3-dione and (R)-(+)-1-phenylethylamine weredissolved in acetonitrile or another inert solvent such as toluene,tetrahydrofuran or cyclohexane, heated to reflux and distilled to removewater. The vinylogous amide(R)-3-[(1-phenylethyl)amino]-2-cyclohexen-1-one was recovered as an oilby rotary evaporation of the solvent.

[0094] Alternatively, (R)-(+)-1-phenylethylamine was added tocyclohexane-1,3-dione in an inert solvent at 20-40° C., held at thattemperature for about 2 hours and then refluxed to remove water.

Example 4 Vinylogous Amides

[0095] Generally vinylogous amides may be made by reacting a substitutedcyclohexane-1,3-dione with a substituted phenylethylamine in an inertsolvent according to the process below.

[0096] Cyclohexane-1,3-dione and a substituted phenylethylamine aredissolved in acetonitrile and heated to refluxing the mixture (81° C.)under Dean-Stark conditions, to remove water. Generally, vinylogousamides may be recovered by evaporation of the solvent to yield theproduct as an oil.

Example 53-[4,4,4-Trifluoro-3-oxo-1-[2-oxo-6-(1-phenylethylinino)cyclohexyl]-butyl]benzonitrile

[0097] 3-(4,4,4-Trifluoro-3-oxo-1-butenyl)benzonitrile of formula mafrom Example 1, was reacted with(R)-(+)-[(1-phenylethyl)amino]-2-cyclohexen-1-one of formula Via fromExample 3, to form3-[4,4,4-trifluoro-3-oxo-1-[2-oxo-6-(1-phenylethylimino)cyclohexyl]butyl]benzonitrileof formula VIIa (a 1,5-diketone), according to the following scheme:

[0098] The α,β-unsaturated ketone (IIIa, 1.0 equivalent) was added to asolution of vinylogous amide (VIa, 1.0 equivalent) in acetonitrile sothat the volume-ratio of acetonitrile to α,β-unsaturated ketone wasabout 3.5-1.0. Trimethylsilyl chloride (0.8-1.2 equivalents) was addeddropwise over 1-30 minutes and the solution heated and maintained at40-50° C., for 12 hours or more to yield the 1,5-diketone.

Example 6(−)-4-(3-Cyanophenyl)-2-triluoromethyl-4,6,7,8-tetrahydro-5(1H)-quinolone

[0099](−)₄-(3-Cyanophenyl)-2-trifuoromethyl-4,6,7,8-tetrahydro-5(1H)-quinolonewas made by converting the 1,5-diketone of formula VIIa, from Example 5,to a hemiaminal of formula VIIb, and thence to(−)-4-(3-cyanophenyl)-2-trifluoromethyl4,6,7,8-tetrahydro-5(1H)-quinoloneof formula VIIIa (a 1,4-dihydropyridine), according to the followingscheme:

[0100] The solution from example 5 was cooled, aqueous ammonia (at least10.7 equivalents) was added and the mixture heated to 40-60° C., for5-17 hours to generate the hemiaminal. VIIb. The reaction mixture wasthen cooled to 20° C., and an acid selected from methane sulfonic acid,trifluoroacetic acid, acetic acid, para-toluene sulfonic acid, amberlyst15, or concentrated hydrochloric acid (5-8 equivalents) was slowly addedin small portions over at least 30 minutes while maintaining thetemperature at 0-30° C. The organic solution was brine-extracted andthen heated to reflux for 4-10 hours to convert the hemiaminal to the1,4-dihydropyridine. The acetonitrile was removed and replaced withdichloromethane, which was washed first with water and then with aqueoussodium hydroxide. The dichloromethane was evaporated, the solid residuetaken up in acetonitrile, the solution concentrated and cooled tocrystallize the title compound which was recovered by filtration.

Example 7 Process for making of3-(4,4,4-trifluoro-3-oxo-1-butenyl)benzonitrile

[0101] A standard 4-necked 1000 mL round bottomed flask (vessel A)equipped with overhead stirrer, condenser and temperature probe, ischarged with 3-cyanobenzaldehyde (30.0 g at 100%, 0.229 mole, 1.0equivalent) under a slow stream of nitrogen;

[0102] dichloromethane (120 mL, 4 volumes) is charged into vessel A,with agitation and the mixture allowed to stir for 10-30 minutes at20-30° C.;

[0103] the reaction mixture is cooled to 0-10° C.;

[0104] a pressure-equalized dropping funnel (Vessel B) is charged withpyrrolidine (17.9 g at 100%, 0.252 mole, 1.1 equivalents) which istransferred into vessel A over about 30 minutes at 0-10° C.;

[0105] vessel B is line washed with dichloromethane (15 mL, 0.5 volumes)into vessel A which is then stirred for about 30 minutes at 0-10° C.;

[0106] a pressure-equalized dropping funnel (Vessel C) is charged with1,1,1-trifluoroacetone (31.01 g at 100%, 0.275 mole, 1.2 equivalents)which is transferred into vessel A over 30-60 minutes at −5 to 10° C.;

[0107] vessel A is stirred for 3-5 hours at −5-10° C. and sampled toensure that the reaction is complete;

[0108] a pressure-equalized dropping funnel (Vessel D) is charged withtrifluoroacetic acid (31.35 g at 100%, 0.275 mole, 1.2 equivalents)which is transferred to vessel A over 30-90 minutes at −5 to 10° C.;

[0109] vessel A is stirred at −5 to 10° C. for 2-10 hours, then allowedto slowly warm to 20-30° C. in about 5 hours or overnight;

[0110] the mixture is assayed to ensure that the reaction is complete;

[0111] water (150 mL (about 5 volumes)) is charged into vessel A and thevessel agitated for about 20 minutes and the mixture allowed to separateinto two phases;

[0112] the lower organic phase is recovered and re-extracted twice againwith water (150 mL) and the organic dichloromethane-containing phasecharged into vessel A;

[0113] vessel A is set for atmospheric distillation under a slow streamof nitrogen and ⅔ of the flask volume is distilled off;

[0114] tert-amylmethylether (150 mL, 5 volumes) is charged into vessel Aand the contents are set to distill at atmospheric pressure;

[0115] distillation is continued until the volume in vessel A isapproximately 80 mL when the vacuum is released and the contents areheated to 45-60° C.;

[0116] a pressure-equalized dropping funnel (Vessel E) is charged withisohexane (150 mL, (about 3.5-6 volumes)) which is charged into vessel Aover 40 minutes;

[0117] the contents of vessel A are maintained at 45-60° C. for afurther 60 minutes, then ramp-cooled over 30-90 minutes to 5-22° C., andthe reaction mixture is stirred overnight;

[0118] the contents of vessel A are cooled to −3 to 8° C. for about 3hours or longer;

[0119] the resultant crystalline solid % α,β-unsaturated ketone isrecovered by filtration;

[0120] the filter cake is fully deliquored and dried in a vacuum oven at50° C. until constant weight is achieved.

Example 8 Process for Making a 1,5-Diketone

[0121] A vinylogous amide in acetonitrile (2.1 volumes, 1 equivalent) ischarged into a clean dry 500 mL flask, (Vessel A), inerted undernitrogen;

[0122] an α,β-unsaturated ketone (1 equivalent) is charged portionwiseinto vessel A;

[0123] acetonitrile (1.4 volumes) is charged into vessel A;

[0124] trimethylsilylchloride (0.82 equivalent) is charged into vessel Adropwise over about 30 minutes while keeping the temperature at 15-25°C.;

[0125] vessel A is heated at a rate of about 0.5° C. per minute to atemperature of about 45° C. and maintained at that temperature for 24hours;

[0126] vessel A containing the 1,5-diketone is cooled to 20° C., orless.

Example 9 Process for Converting a 1,5-Diketone to a 1,4-Dihydropyridine

[0127] The reaction mixture from Example 8, is transferred into a 1000mL 4-necked flask, vessel A;

[0128] 35% aqueous ammonia (at least 10.7 equivalents) is charged intovessel A dropwise over 30 minutes while maintaining the temperature at20-30° C.;

[0129] vessel A is heated at a rate of 0.5° C. per minute to atemperature of 40-60° C. and held in that temperature range for 17hours;

[0130] the temperature of the batch is then held at 55° C. for about 1hour and then cooled to 5-8° C. over about 1.5 hours;

[0131] concentrated hydrochloric acid (about 6.7 equivalents) is chargedinto vessel A dropwise over about 30 minutes while maintaining thetemperature at 0-30° C.;

[0132] brine (1.3 volumes) is charged into vessel A;

[0133] vessel A is agitated, allowed to settle and the lower aqueousphase is discarded keeping the interface with the upper phase;

[0134] the upper acetonitrile phase is heated to reflux, maintained atreflux for 6 hours and allowed to cool overnight;

[0135] solid material is removed by filtration and the liquor is reducedto a semi-solid by rotary evaporation;

[0136] dichloromethane (at least 4 volumes) and water (at least 4volumes) is added to the semi-solid residue and the mixture returned tovessel A;

[0137] the mixture is agitated and the lower phase is recovered;

[0138] the organic phase is extracted with water (at least 4 volumes)and recovered;

[0139] the organic phase is twice extracted with aqueous NaOH (at least4 volumes) and then with water (at least 4 volumes) and recovered;

[0140] the organic phase is distilled at a jacket temperature of 60° C.,until flow drops to a slow trickle and the head temperature falls to 25°C.;

[0141] vessel A is charged with acetonitrile (0.6-0.8 volumes) anddistilled at a jacket temperature of 87° C., until the volume is reducedto 0.2-0.3 volumes;

[0142] the contents of vessel A are slowly cooled to −5 to 10° C.;

[0143] the formed solid is recovered, washed with methyl tert-butylether (0.1-0.2 volumes) and dried under vacuum below 70° C.

1. A process for making an α,β-unsaturated ketone, said processcomprising: reacting an aldehyde and a secondary amine selected frompyrrolidine, piperidine, morpholine and diethylamine, in dichloromethaneat 0-10° C. to form an intermediate; adding a ketone, and reacting saidintermediate with said ketone by adding trifluoroacetic acid whilemaintaining the temperature at 0-10° C., to form an α,β-unsaturatedketone.
 2. The process according to claim 1, wherein said secondaryamine is pyrrolidine.
 3. The process according to claim 1, wherein: saidaldehyde is a compound of formula I

 wherein: R¹ is selected from (C₁-C₆)alkyl, or aryl where any alkyl oraryl moiety is unsubstituted or mono-, di- or tri-substituted withmoieties independently selected from hydroxy, halo, and cyano; or R¹ isa group of formula X,

 wherein: G and J are independently selected from hydrogen, hydroxy(C₁-C₄)alkoxy, nitro, cyano, (C₁-C₄)fluoroalkyl, (C₁-C₄)fluoroalkoxy,halo, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl, phenyl and (C₁-C₄)alylsulphonyl, orG and J taken together are (C₁-C₄)alkylenedioxy; or R¹ is 2-thienyl4-substituted, 5-substituted or 4,5-substituted with E, or 3-thienyl orfuryl 5-substituted with E where E is independently selected from agroup consisting of nitro, cyano, halo, (C₁-C₆)alkyl,(C₁-C₄)alkyl-sulphonyl and 2-thienyl, where “halo” includes bromo,chloro, fluoro and iodo; or R¹ is a 2-pyridyl 4,5-substituted,5-substituted or 5,6-substituted with E; or R¹ is a 3-pyridyl6-substituted with E; or R¹ is a 4-pyridyl 2-substituted with E; saidketone is a compound of formula II,

 wherein: R² is selected from hydrogen, (C₁-C₆)alkyl and mono-, di- ortri-halo(C₁-C₄)alkyl; R³ is selected from hydrogen, cyano, (C₁-C₆)alkyl,(C₁-C₆)fluoroalkyl and ethanoyl; or R² and R³, when taken together, forma substituted or unsubstituted (C₁-C₆)cycloalkyl moiety, and saidα,β-unsaturated ketone is a compound of formula III,


4. The process according to claim 3, wherein in said compounds offormula I, II and III: R¹ is selected from (C₁-C₆)alkyl, or aryl whereany foregoing alkyl or aryl moiety can be substituted with hydroxy,halo, or cyano; R² is selected from mono-, di- or tri-halo(C₁-C₄)alkyl;R³ is selected from hydrogen, cyano, (C₁-C₆)alkyl, (C₁-C₆)fluoroalkyland ethanoyl, and R⁴ and R⁵ are independently selected from hydrogen ormethyl.
 5. The process according to claim 3, wherein in said compoundsof formula I, II and III: R¹ is selected from methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,3-methylbutyl, 1-ethylpropyl, hexyl, 4-methylpentyl, phenyl,3-methoxyphenyl, 3-nitrophenyl, 3-cyanophenyl, 3-trifluoromethylphenyl,3-trifluoromethylfcyanophenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl,3-bromo-4-fluorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, and3,4-methylenedioxyphenyl; R² is selected from methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl and trifluoromethyl;R³ is selected from hydrogen, cyano and ethanoyl, and R⁴ and R⁵ areselected from hydrogen and methyl.
 6. The process according to claim 3,wherein: said aldehyde is 3-cyanobenzaldehyde, and said ketone is1,1,1-trifluoroacetone.